Heart failure is a state, in which the pump function of a heart deteriorates due to various causes, and a blood volume corresponding to the demand for oxygen in peripheral major organs cannot be absolutely or relatively pumped, and a state, in which congestion is caused in lung or systemic venous system or in both systems and a disorder is caused in daily life. QOL of patients with heart failure is remarkably deteriorated due to the symptoms such as exertional dyspnea, shortness of breath, malaise, decrease in urine volume, limb edema and hepatomegaly.
It is estimated that there are currently more than a million patients with heart failure in this country, and the number is increasing for certain year by year due to the recent westernization of dietary habits and the aging society. Further, there are several million patients with heart failure each in the U.S. and in Europe, and the number is expected to further increase in the future. In addition, heart failure is known to be one of the diseases with poor prognoses. For example, it is reported that the patients with heart failure as a whole have a 50% chance of surviving five years and the patients with severe heart failure have a 30% chance of surviving three years, and heart failure shows the prognosis comparable to those of cancers. Thus, heart failure is placed as an extremely severe disease due to the large number of the patients and the poor prognosis.
In treating heart failure, the therapeutic strategy is generally decided depending on whether the pathological condition of the heart failure is chronic or acute.
So-called chronic heart failure, which refers to the chronic pathological change, is heart failure showing progressive exacerbation for a long time, and is known to be caused associated with for example myocardial disease or valvular disease. As the treatment of chronic heart failure, for example, an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, a β-blocker, digitalis, a diuretic agent, an aldosterone antagonist or the like is administered.
On the other hand, so-called acute heart failure, which refers to the acute pathological change, is a state, in which the ventricular filling pressure increases because the compensation of the pump function of a heart rapidly falls down, and perfusion failure to main organs occurs thereby rapidly causing symptoms and signs based thereon. As the treatment of acute heart failure, a diuretic agent or a vasodilator for the intravenous administration is administered for removing the symptoms of congestion and dyspnea as soon as possible, and, when hypoperfusion is observed in particular, a cardiotonic agent such as dopamine or dobutamine is used.
As the pathological condition of heart failure, only systolic heart failure developing left ventricular systolic functional failure has been the focus of attention so far. However, heart failure, in which the left ventricular ejection fraction (LVEF, indication for the left ventricular systolic force) is normal or only slightly deteriorated, namely so-called diastolic heart failure, is recently regarded as problems.
Diastolic heart failure is known to be common among women and elderly people, in particular among patients with hypertension or diabetes. The anatomical characteristics of hearts of patients with diastolic heart failure are the concentric hypertrophy, and the ventricular wall thickens and the myocardial fibrillization is progressed, although there is no difference in the heart size in comparison with healthy individuals. As a result, the cardiac ventricle cannot dilate sufficiently during diastole and it constricts before the filling blood, and thus a sufficient blood volume cannot be pumped.
Patients with diastolic heart failure account for about a half of the whole heart failure patients. Although their prognoses are comparable to those of systolic heart failure patients, most therapeutic agents which are currently used for heart failure patients are agents, which have been clinically tested for systolic heart failure patients with lowered LVEF. There is no medicament, which has an effect to relieve diastolic functional failure and which has been proven to improve the prognoses of diastolic heart failure patients.
For the acute exacerbation phase of diastolic heart failure patients, a diuretic agent or a venodilatory vasodilator is used, as in the case of systolic heart failure patients. However, when such a medicament is administered to a patient with diastolic heart failure, there are problems in that the cardiac output and the blood pressure tend to decrease, or the patient is repeatedly hospitalized due to the higher frequency of recurrence in comparison with a systolic heart failure patient.
Further, it is said that most of the patients, who were diagnosed with systolic heart failure, actually suffer from left ventricular diastolic dysfunction.
Among the existing medicaments used for the treatment in the acute phase, there is no medicament which selectively relieves left ventricular diastolic dysfunction, and there are patients with symptoms of lung congestion or dyspnea, which are not relieved, or which need a long time to be improved. Thus, a new therapeutic agent is desired.
As described above, at this point, there is no effective therapeutic method for diastolic heart failure or left ventricular diastolic dysfunction, and thus the development of a new therapeutic means is urgently needed.
On the other hand, 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof is a selective agonist for EP4, which is a receptor subtype of prostaglandin E2, and is reported to be effective for immune diseases (autoimmune diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Sjogren's syndrome, chronic rheumatoid arthritis and systemic lupus erythematosus, rejection after organ transplantation, and the like), asthma, neuronal cell death, arthritis, lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis (acute nephritis and chronic nephritis), renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock, gastric ulcer, peptic ulcer such as duodenal ulcer, stomatitis, baldness, alopecia, loss in bone mass, sleep disorder, thrombosis, lower urinary tract symptom, hyperkalemia, neurodegenerative disease, and the like (please refer to Patent Documents 1, 2, 3 and 4).
Further, it is disclosed that a selective agonist for EP4 shows a renal vasodilation activity and thus is effective for renal insufficiency or renal dysfunction, or a state such as congestive heart failure caused by renal insufficiency or renal dysfunction (please refer to Patent Document 5).
On the other hand, it is also known that a compound having an EP4 antagonistic action acts therapeutically on heart failure (please refer to Patent Document 6).
As described above, there are conflicting findings as to whether EP4 works promotionally or inhibitory on the pathological condition of heart failure, and thus the situation was that there was no certain scientific findings. As a matter of course, there was no description or suggestion that 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof, which is an EP4 agonist, has an effect to improve left ventricular diastolic function, and acts therapeutically on heart failure patients, in particular diastolic heart failure patients.